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Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 1 to 25 of 40. This is the beginning of the thread.
Posted by bleauberry on August 13, 2010, at 19:33:52
What is treatment resistant depression? Well, to most of us, it is one that does not respond very well to various methods of manipulating serotonin, norepinephrine, dopamine, gaba, and glutamate.
Endogenous endorphin deficiency. That is a good keyword phrase to do some google searching and reading. The endorphin/opioid system is a major player in mood, but is practically 100% ignored in psychiatry. All the hoopla is on serotonin and friends.
Very easy to test if this is your kind of depression or not. And much easier to treat once it has been identified. Simple things like LDN and/or DLPA or DPA. Sometimes PEA. In tough cases, maybe tramadol, vicadin, hydrocodone, those these are better for diagnostic tools than longterm treatment IMO.
Anyway, there is some good reading out there on this topic and you might find it describes you. I hope you find something helpful. When we've done everything we can imagine for our serotonin and buddies, I think it makes sense to look at what we didn't try to treat....the major player endorphins.
We have two choices:
1. Test the hypothesis to confirm it or rule it out within a time period of 1 to 3 days. If positive, then we know where to focus for rapid recovery. If negative, then we are back to the serotonin and friends stuff and taking a look at other things like infection and toxins.
2. Keep beating the bush on serotonin and friends as far as we can see into the future with fingers crossed we'll get lucky someday.Treatment resistance to me means we haven't hit the right chemistry yet. The one we almost always miss is a huge player, the endogenous endorphins.
Posted by linkadge on August 13, 2010, at 19:42:23
In reply to Treatment Resistant Depression., posted by bleauberry on August 13, 2010, at 19:33:52
I think its more complicated than that. I think that TRD is more hardwired.
"You can mess around all you want with serotonin, norepinephrine, dopamine etc. but if you don't have the right circutry in place, its not going to do anything" - a quote by Dr. Manjii.
I think TRD is probably related to mitochondrial decay, glial reductions, prefronal atrophy, decreased limbic interconnectivity, enlarged amygdala volume, decreased cortical grey matter, white matter hyperintensities, vascular insufficiancy etc. etc.
I personally think its a myth to believe that some magic chemical is going to come along and make it all better. It may take years of rehabilitative therapty for the brain to overcome such alterations.
Linakadge
Posted by Phillipa on August 13, 2010, at 20:17:54
In reply to Re: Treatment Resistant Depression., posted by linkadge on August 13, 2010, at 19:42:23
Uh oh my newsletter today has a newsarticle on how they new year will bring drastic changes with opiods as they are deemed dangerous. Let me see if can retrive in deleted and copy and paste here. Phillipa
Posted by Phillipa on August 13, 2010, at 20:26:17
In reply to Re: Treatment Resistant Depression., posted by Phillipa on August 13, 2010, at 20:17:54
Not good news for controlled meds or those on them. Phillipa
From Medscape Medical News
FDA Planning Final Opioid Recommendations by 2011
Allison GandeyAugust 13, 2010 The US Food and Drug Administration (FDA) reports that new opioid recommendations will be unveiled early next year. The agency told Medscape Medical News the risk evaluation and mitigation strategies, known as REMS, are scheduled to be approved in 2011, with roll out and implementation to follow.
Regulators had been projecting a summer release, but a recent advisory committee vote against the agency's proposal was a blow to the plan. Most committee members agreed that safety measures for opioids are urgently needed but voiced concern that the current approach does not go far enough to protect the public.
According to some reports, there are more deaths from opioid overdoses than from heroin and cocaine overdoses combined.
"FDA is currently reviewing the input from the advisory committee and the public," said Karen Mahoney, from the agency's Center for Drug Evaluation and Research. "We have not yet made any final decisions on the REMS program. Once final decisions are made, FDA will communicate these requirements to the manufacturers, and they will have up to 120 days to submit a program for FDA's review and approval."
Herbert Neuman, MD, vice president of medical affairs and chief medical officer at Covidien Pharmaceuticals, says he is eagerly awaiting the new plan. The company already has REMS in place for hydromorphone extended-release (Exalgo). "We will modify our approach to comply with whatever the requirements will be," Dr. Neuman said during an interview, adding that he looks forward to the clarity a final decision will afford.
The advisory committee's 25 to 10 vote against the first proposal, which was largely favored among industry, sent a strong message to regulators that new recommendations will require more teeth.
The plan will alter the prescribing landscape for opioid therapies and is expected to have important implications for an estimated 4 million patients.
Mandatory Education
Advisory committee members recommended mandatory training for prescribers. They called on Congress to initiate new legislation to link physician education to the existing Drug Enforcement Administration registration system. More than 1 million clinicians are currently registered to prescribe opioids.
The committee, led by Jeffrey Kirsch, MD, from the Oregon Health and Science University in Portland, argued that the overwhelming public health problem of opioid misuse is in part beyond the regulatory control of the FDA and will require a multidisciplinary approach.
It is a view shared by many, including Seddon Savage, MD, president of the American Pain Society, who recently told Medscape Medical News that Drug Enforcement Administration involvement is "the best long-term solution."
Perry Fine, MD, president elect of the American Academy of Pain Medicine, says he agrees. "The Drug Enforcement Administration is already involved, so it makes sense to include education." Dr. Fine points out that in the absence of a well-designed uniform curriculum focused on opioid therapies in medical schools, continuing education is necessary. "We need to learn about opioids in the same way we learn about sterile technique or appropriate use of antibiotics," he said.
The advisory committee called on regulators to add immediate-release drugs to the current plan, which presently includes only extended-release and long-acting formulations.
All Controlled Drugs
Dr. Fine has concerns about whether all drug schedules will be included in the REMS, or just schedule II products. "This wasn't brought up by the FDA or the advisory committee, and it could have a chilling effect on prescriptions," he said. If only schedule II compounds have more stringent requirements, then physicians may opt out by prescribing less-monitored alternatives. "They may not prescribe the most useful drug, and focus instead on other nonmedical issues, putting patients in an even more vulnerable position than they already are in."
Dr. Fine says electronic health records may help a patient's electronic file could record all physician visits and prescription refills. "This is a concern not only with opioids, but with all medications that could have contraindications for a variety of reasons," he noted.
The timeline for the FDA's plan has moved more than once. Dr. Fine says this is not surprising. "It is an extraordinary undertaking that will have enormous implications, and it is important to carefully weigh the consequences of any proposed action," he said. "It's important the FDA does something reasonable and responsible."
Posted by violette on August 13, 2010, at 21:08:39
In reply to Treatment Resistant Depression., posted by bleauberry on August 13, 2010, at 19:33:52
Falling in love increases endorphins in the brain. Maybe TRD has something to do with chronic lack of love or emotional connection with oneself or others.
That sounds too simplistic. The alernative hypothesis: without love, a true emotional connection with others or self, the brain, the spirit, shrivels up and dies.
Posted by Phillipa on August 13, 2010, at 21:18:56
In reply to Re: Treatment Resistant Depression. » bleauberry, posted by violette on August 13, 2010, at 21:08:39
What about all the lonely people out there in the world? Phillipa
Posted by ed_uk2010 on August 13, 2010, at 22:35:06
In reply to Treatment Resistant Depression., posted by bleauberry on August 13, 2010, at 19:33:52
>In tough cases, maybe tramadol, vicadin, hydrocodone, those these are better for diagnostic tools than longterm treatment IMO.
In order for something to gain acceptance as a diagnostic tool, its usefulness has to have been scientifically validated. Vicodin is not a diagnostic tool for anything except response to Vicodin :) Opioids frequently produce mood changes, elevation or otherwise, regardless of whether the person who took the drug is suffering from depression or not.
Posted by ed_uk2010 on August 13, 2010, at 22:35:57
In reply to Re: Treatment Resistant Depression., posted by linkadge on August 13, 2010, at 19:42:23
>I think TRD is probably related to mitochondrial decay, glial reductions, prefronal atrophy, decreased limbic interconnectivity, enlarged amygdala volume, decreased cortical grey matter, white matter hyperintensities, vascular insufficiancy etc. etc.
Sounds like dementia!
Posted by sigismund on August 13, 2010, at 23:02:22
In reply to Re: Treatment Resistant Depression., posted by ed_uk2010 on August 13, 2010, at 22:35:06
>In tough cases, maybe tramadol, vicadin, hydrocodone, those these are better for diagnostic tools than longterm treatment IMO.
In most cases there will be a positive result.
Like my shrink said to me when I said I'd look out for some tandospirone in Vietnam
'Or something really useful, like opium!'
but then he, like me, is sceptical about all this.
Posted by sigismund on August 13, 2010, at 23:07:54
In reply to Re: Treatment Resistant Depression., posted by sigismund on August 13, 2010, at 23:02:22
It has a good effect on me, anyway.
I'm so glad of some intelligent company that I'm on my best behaviour.
He says 'Who doesn't feel better on amphetamine?'
So I never ask him for any, beyond the usual
'I'd dearly love to have a bottle of Dexedrine in the back of the cupboard for the 1001 awful events I have to face which include (from time to time) getting up.'He has organised it well, by also saying that he was taught not to do polypharmacy.
Posted by floatingbridge on August 14, 2010, at 2:37:58
In reply to Treatment Resistant Depression., posted by bleauberry on August 13, 2010, at 19:33:52
Unofficially, seems that opoid response could be noticed (and noted) in a patient. We know from previous babble threads that not all respond. Well, I guess that could mean the person does not 'process' opoids (oh please forgive the complete lack of scientific language). So I guess I just wrote myself out of that :)
So, exercise, (good) sex, meditation, love, laughter increase endorphines. Easier to accomplish when feeling good. Anything else?
LDN?
Posted by SLS on August 14, 2010, at 4:43:23
In reply to Re: Treatment Resistant Depression., posted by linkadge on August 13, 2010, at 19:42:23
> I think TRD is probably related to mitochondrial decay, glial reductions, prefronal atrophy, decreased limbic interconnectivity, enlarged amygdala volume, decreased cortical grey matter, white matter hyperintensities, vascular insufficiancy etc. etc.
You've been reading again!
No fair!
Good stuff.
- Scott
Posted by bleauberry on August 14, 2010, at 8:06:05
In reply to Re: Treatment Resistant Depression., posted by linkadge on August 13, 2010, at 19:42:23
I totally agree with you LInk. The things you mentioned though are so hard, if not impossible, to identify, diagnose, or validate. But doing all that with the endorphin system, well, even a caveman could do it. My point is I don't get it...why all the hoopla on selected neurotransmitters as if they were everything there is in depression...but no mention of the big player endorphins. And no mention of all the things you listed either. Instead, keep pounding the serotonin-n-friends drugs despite they fail one after another after another. Kind of like trying to sift for gold in about a 10 foot area of a stream but not daring to go further upstream or downstream. So what if you can't find any gold in that 10 feet, keep looking there. Ya know? I'm just saying the endorphin system is a big player but that unlike the other systems it is very easy to test.
> I think its more complicated than that. I think that TRD is more hardwired.
>
> "You can mess around all you want with serotonin, norepinephrine, dopamine etc. but if you don't have the right circutry in place, its not going to do anything" - a quote by Dr. Manjii.
>
> I think TRD is probably related to mitochondrial decay, glial reductions, prefronal atrophy, decreased limbic interconnectivity, enlarged amygdala volume, decreased cortical grey matter, white matter hyperintensities, vascular insufficiancy etc. etc.
>
> I personally think its a myth to believe that some magic chemical is going to come along and make it all better. It may take years of rehabilitative therapty for the brain to overcome such alterations.
>
> Linakadge
>
>
>
>
>
Posted by bleauberry on August 14, 2010, at 8:25:18
In reply to Re: Treatment Resistant Depression., posted by ed_uk2010 on August 13, 2010, at 22:35:06
Well, this is not really true. Yes, opioids do exert psychoactive effects. However, those effects differ. Some people become dysphoric. They don't need more endorphins help. Some people become euphoric...they also do not need endorphin help...they are just getting high from the excess. Other people however go from depressed to normal...pure normal...not high, not drugged, not euphoric, just plain normal...THAT is an easy diagnosis.
As far as the acceptance of something as a diagnostic tool, I personally could care less what academia accepts or not. They are so far removed from the real world they live in theory textbooks and statistics. More often than not, their conclusions of today are proven wrong 10 years from today. Many diagnostic tests of all kinds have errors, false negatives, false positives, and are prone to subjective interpretation or faulty interpretation. I don't trust em. They are not the gods many people see them as. They are not the authority and certainly not mine. If someone wants to wait for something to become "accepted" or "scientifically validated" (even there full of errors) they are going to probably remain ill for a very long time waiting. I guess overall what I am saying is that our depression and our health is in nobody's hands except our own. It is no one else's baby. A doctor can sure help and guide things, but it is not his baby. It's your life, my life, and we are responsible. For me to not take action in ruling in or ruling out something as simple as the endorphin hypothesis is irresponsible. IMO.
Vicodin is a diagnostic tool. It can rule in or rule out a suspect chemistry by observing the resulting behavior comparing pre-drug and during-drug. In the manner described above. Two doctors at my post op followup said they have seen papers recently of opioids treating depression, so they were not surprised at the idea. To them, it is already scientifically validated because it was in their medical journals, and to them is probably not quite accepted but at least in an open minded direction. No matter how much something is validated, there will always be a group of critics claiming the opposite. In the meantime, people stay sick.
If someone just doesn't want to mess with a full blown opioid, fine, they can still do some pretty good detective work with DPA, DLPA, LDN. Which years into TRD makes more sense than yet another antidepressant.
Ok, let's just take your position at face value and accept it. Ok, so someone has TRD, is given vicodin for surgery, experiences profound relief of depression and even some euphoria. Ok, opioids can do that. Doesn't mean anything. Except that...LDN or DLPA have a very high likelihood of coming close to the same result...a patient free of depression...because those substances work on the same chemistry as vicodin. That same patient staying instead with the ssris, antipsychotics, and mood stabilzers, is probably going to remain ill for a long time.
>
> In order for something to gain acceptance as a diagnostic tool, its usefulness has to have been scientifically validated. Vicodin is not a diagnostic tool for anything except response to Vicodin :) Opioids frequently produce mood changes, elevation or otherwise, regardless of whether the person who took the drug is suffering from depression or not.
>
>
Posted by bleauberry on August 14, 2010, at 8:31:19
In reply to Re: Treatment Resistant Depression. » bleauberry, posted by floatingbridge on August 14, 2010, at 2:37:58
> So, exercise, (good) sex, meditation, love, laughter increase endorphines. Easier to accomplish when feeling good. Anything else?
>
> LDN?The ones I am aware of are:
LDN
DLPA
DPA
AccupunctureTramadol is handed out like candy, and gets rave reviews in depression, so that is a possibility as long as someone doesn't mind the word addiction as being a part of living a productive life free of depression. But it has other mechanisms as SNRI, which complicates it. Me, positive response to vicodin, horrible rersponse to tramadol, modest response LDn or DLPA (even modest is a million miles better than all the cocktails were able to achieve).
Posted by ed_uk2010 on August 14, 2010, at 8:58:20
In reply to Re: Treatment Resistant Depression. » ed_uk2010, posted by bleauberry on August 14, 2010, at 8:25:18
>Some people become dysphoric. They don't need more endorphins help.
Some of the people who become dysphoric after a single dose become euphoric after repeated doses. In the same way that response to an SSRI does not prove that a person has serotonin deficiency, response to an opioid does not prove that a person has endorphin deficiency. It's unwise to presume that we understand so much.
>Other people however go from depressed to normal...pure normal...not high, not drugged, not euphoric, just plain normal...THAT is an easy diagnosis.
It's not a diagnosis, it's an assumption - an assumption that endorphin deficiency is the underlying problem. Again, it is unwise to presume that we understand the mechanisms behind such a response. Unfortunately, an excellent acute response to an opioid does not mean that the benefits will last. They might do, or they might not. I think that's the same with just about everything ie. the long term response it impossible to predict with any accuracy.
>Except that...LDN or DLPA have a very high likelihood of coming close to the same result...
I doubt that a response to Vicodin can predict response to LDN or DLPA. LDN, opioid agonists and DLPA have different mechanisms of action. A response to Vicodin might predict a response to say, oxycodone, because these drugs have the same mechanism of action.
>That same patient staying instead with the ssris, antipsychotics, and mood stabilzers, is probably going to remain ill for a long time.
I fully understand the need for new and novel treatments for psychiatric illness. I do not dispute that.
I think you have a tendency to present theory as if it were fact. This is what I disagree with.
Posted by sigismund on August 14, 2010, at 19:14:31
In reply to Re: Treatment Resistant Depression. » bleauberry, posted by ed_uk2010 on August 14, 2010, at 8:58:20
>It's not a diagnosis, it's an assumption - an assumption that endorphin deficiency is the underlying problem. Again, it is unwise to presume that we understand the mechanisms behind such a response. Unfortunately, an excellent acute response to an opioid does not mean that the benefits will last. They might do, or they might not. I think that's the same with just about everything ie. the long term response it impossible to predict with any accuracy.
Just like the neurotransmitter theory of depression?
I said to my shrink that the neurotransmitter hypothesis was dead and he perked up immediately and then we talked about psychopaths in high places.
Posted by emmanuel98 on August 14, 2010, at 19:52:55
In reply to Re: Treatment Resistant Depression. » ed_uk2010, posted by sigismund on August 14, 2010, at 19:14:31
I was in the hospital and doing a two-week washout from ensam so I could start parnate. I was severely depressed. I asked the p-doc there if I could try suboxone. Opiates kept my depression at bay for five years (self-precribed, using higher and higher dosages. I got off them by working with a suboxone doctor). Suboxone can't be used to OD (contains naltrexone) and it's hard to use higher and higher dosages also because of the naltrexone and because it's taken sublingually and because precriptions are carefully monitored. She said she would consult about it, but by that time, I was on parnate and felt fine within 48 hours.
Posted by bleauberry on August 15, 2010, at 12:06:34
In reply to Re: Treatment Resistant Depression. » bleauberry, posted by ed_uk2010 on August 14, 2010, at 8:58:20
I agree with everything you have said. In fact, everything stated could apply equally as well to a discussion of any other neurotransmitter or drug. But all that was off the path. It appears that the primary body of the message was completely missed. Took some sidepaths and completely lost the main road.
> >Some people become dysphoric. They don't need more endorphins help.
>
> Some of the people who become dysphoric after a single dose become euphoric after repeated doses. In the same way that response to an SSRI does not prove that a person has serotonin deficiency, response to an opioid does not prove that a person has endorphin deficiency. It's unwise to presume that we understand so much.
>
> >Other people however go from depressed to normal...pure normal...not high, not drugged, not euphoric, just plain normal...THAT is an easy diagnosis.
>
> It's not a diagnosis, it's an assumption - an assumption that endorphin deficiency is the underlying problem. Again, it is unwise to presume that we understand the mechanisms behind such a response. Unfortunately, an excellent acute response to an opioid does not mean that the benefits will last. They might do, or they might not. I think that's the same with just about everything ie. the long term response it impossible to predict with any accuracy.
>
> >Except that...LDN or DLPA have a very high likelihood of coming close to the same result...
>
> I doubt that a response to Vicodin can predict response to LDN or DLPA. LDN, opioid agonists and DLPA have different mechanisms of action. A response to Vicodin might predict a response to say, oxycodone, because these drugs have the same mechanism of action.
>
> >That same patient staying instead with the ssris, antipsychotics, and mood stabilzers, is probably going to remain ill for a long time.
>
> I fully understand the need for new and novel treatments for psychiatric illness. I do not dispute that.
>
> I think you have a tendency to present theory as if it were fact. This is what I disagree with.
>
Posted by ed_uk2010 on August 15, 2010, at 13:50:28
In reply to Re: Treatment Resistant Depression. » ed_uk2010, posted by bleauberry on August 15, 2010, at 12:06:34
>But all that was off the path. It appears that the primary body of the message was completely missed. Took some sidepaths and completely lost the main road.
I think the message is that we should be willing to try something different and novel when the usual treatments haven't helped? Trying the 6th SSRI after 5 haven't worked isn't likely to be effective!
Posted by linkadge on August 15, 2010, at 21:15:48
In reply to Re: Treatment Resistant Depression. » linkadge, posted by ed_uk2010 on August 13, 2010, at 22:35:57
>Sounds like dementia!
Exactly.
Linkadge
Posted by linkadge on August 15, 2010, at 21:23:25
In reply to Re: Treatment Resistant Depression. » bleauberry, posted by ed_uk2010 on August 15, 2010, at 13:50:28
Opiates like codiene and morphine act as fairly potent sigma-1r agonists. Sigma agonists have documented antidepressant, anxiolytic and cognitive enhancing effects.
Whose to say that the "AD" effect of opiates is not related to other targets of select opiates?
As eluded to, some studies suggest increased opioid like activity in depression. Socially defeated "depressed" animals show increased MU opioid neurotransmission.
Linkadge
Posted by Phillipa on August 15, 2010, at 21:34:33
In reply to Re: Opiates as sigma agonists, posted by linkadge on August 15, 2010, at 21:23:25
All I know is one percocet had me laughing and that is all I took the days was on them. Dumb docs. Phillipa
Posted by SLS on August 16, 2010, at 4:55:08
In reply to Re: Opiates as sigma agonists, posted by linkadge on August 15, 2010, at 21:23:25
> As eluded to, some studies suggest increased opioid like activity in depression. Socially defeated "depressed" animals show increased MU opioid neurotransmission.
Do you think that this might be an effect secondary to the stimulus rather than a cause of the depression? Perhaps the numbing effect of opioidergic neurotransmission is protective against psychic pain. Just thinking...
- Scott
Posted by violette on August 16, 2010, at 8:33:24
In reply to Re: Opiates as sigma agonists » linkadge, posted by SLS on August 16, 2010, at 4:55:08
"Perhaps the numbing effect of opioidergic neurotransmission is protective against psychic pain. Just thinking"
That's true, Scott. Unsure if this is in context with what Linkadge said (?), but it is true that the brain releases opoids when psychic pain is too overwhelming - dissociation is a primary example.
If at a young age you experienced overwhelming psychic pain leading to repeated dissociation (I have) the brain's 'hardwiring' does not develop as a normal child's.
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